What is Systemic Sclerosis (SSc)?

Systemic sclerosis (SSc; also known as scleroderma) is a chronic autoimmune connective tissue disease characterised by excessive Collagen deposition in the skin and internal organs such as the gastrointestinal tract, kidney, heart and lung.^{1, 2} Symptoms result from vascular dysfunction, Inflammation and progressive Fibrosis which lead to occlusion of the microvasculature.

Depending on the pattern of tissues and organs affected, Autoantibody specificities and clinical findings, SSc is commonly divided into two major subsets known as diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc). LcSSc is defined by skin thickening in areas solely distal to the elbows and knees, with or without facial effects, such as Telangiectases. In contrast, dcSSc is defined by the presence of skin thickening that is proximal, as well as distal, to the elbows and knees, with or without facial or truncal effects (Figure 1). On the base of diffuse fibrotic involvement (skin and internal organ), disease is frequently more severe in patients with dcSSc.

Figure 1. The two major subsets of SSc - areas of skin involvement are shown in blue

What is the pathogenesis of SSc?

The pathogenesis of SSc is complex and, as yet, not completely understood. A range of environmental and genetic factors may contribute, but in general the causes of SSc remain to be elucidated. However, SSc does have three cardinal features (Figure 2):
• Vasculopathy (damage to and remodeling of the blood vessels)
• inflammation/autoimmune activation.
• fibrosis (formation or development of excess fibrous connective tissue)

Figure 2. The pathogenesis and cardinal features of SSc³

[Adapted from Charles et al 2006]

What is vascular dysfunction and remodeling?

Whatever the underlying cause of the disease, vascular dysfunction appears to be an early event in the pathophysiology of SSc and is central to the serious complications of SSc. This can result in clinical manifestations of impaired function, such as Raynaud's phenomenon. Some patients will progress and structural changes and vascular remodeling can occur.

Damage to the endothelial cells is key to the development of vasculopathy, and is associated with immune-mediated cell damage (i.e. anti-endothelial cell antibodies), platelet activation and an imbalance between the production of the vasodilatory and vasoconstrictory agents essential for normal blood vessel structure and function.

Vascular remodeling itself involves all layers of the vessel wall and is characterised by proliferative and obstructive changes involving many cell types, including endothelial cells, smooth muscle cells and Fibroblasts. Hypertrophy of the endothelial cells of the intima and proliferation of the vascular smooth muscle cells of the media cause thickening of the blood vessel walls. Eventually, in situ thrombosis occurs, severely affecting the function of the blood vessels and impairing blood flow. These features are also common to PAH (Figure 3).

Figure 3. The nature of the vascular dysfunction in SSc

The underlying vascular dysfunction is shared by several of the manifestations of SSc, including PAH, scleroderma renal crisis and, the most visible manifestation, digital ulceration (Figure 4).

Figure 4. The nature of the vascular dysfunction in SSc

What organs are involved in SSc?

Skin is the most overtly involved organ in SSc. However, a number of internal organs can also be affected (Figure 5). Vascular dysfunction and remodeling in the lungs result in PAH and Interstitial lung disease (ILD). The same processes in the kidneys can result in scleroderma renal crisis, a once almost universally fatal manifestation of SSc. The heart can also be affected and the most commonly affected organ is the gastrointestinal tract, which is involved in > 90% of patients with SSc.

Figure 5. Organ involvement in Systemic sclerosis (IcSSc and dcSSc)

References
1. Mouthon L, Guillevin L, Humbert M. Pulmonary arterial hypertension: an autoimmune disease? Eur Respir J 2005;26(6):986-8.
2. Denton CP, Black CM. Targeted therapy comes of age in scleroderma. Trends Immunol 2005;26(11):596-602.
3. Charles C, Clements P, Furst DE. Systemic sclerosis: hypothesis-driven treatment strategies. Lancet 2006; 367: 1683−1691.